PLANTS THAT FIGHT CANCER - PART 3 pps

52 Spiridon E. Kintzios et al. Other biochemical effects that have been associated with VBL and VCR include: competition for transport of amino acids into cells; inhibition of purine biosynthesis; inhibition of RNA, DNA and protein synthesis; inhibition of glycolysis; inhibition of release of histamine by mast cells and enhanced release of epinephrine; and disruption in the integrity of the cell membrane and membrane functions. Microtubules are present in eukaryotic cells and are vital to the performance of many critical functions including maintenance of cell shape, mitosis, meiosis, secretion and intracellular transport. VBL and VCR exert their antimicrotubule effects by binding to a site on tubulin that is distinctly different from the binding sites of others. They have a binding constant of 5.6 ϫ 10 Ϫ5 M and initiate a sequence of events that lead to disruption of microtubules. The binding of VBL and VCR to tubulin, in turn, prevents the polymerization of these subunits into microtubules. The net effects of these processes include the blockage of the polymerization of tubulin into microtubules, which may eventually lead to the inhibition of vital cel- lular processes and cell death. Although most evidence suggests that mitotic arrest is the principal cytotoxic effect of the alkaloids, there is also evidence that suggests that the lethal effects of these agents may be attributed in part to effects on other phases of the cell cycle. The alkaloids also appear to be cytotoxic to nonproliferat- ing cells in vitro and in vivo in both G1 and S cell cycle phases. In other words, VBL and VCR work by inhibiting mitosis in metaphase (Danieli, 1998; Garnier et al., 1996). ● Studies with germinating seedlings have suggested that alkaloid biosynthesis and accumulation are associated with seedling development. Studies with mature plants also reveal this type of developmental control. Furthermore, alkaloid biosynthesis in cell suspension cultures appears to be coordinated with cytodifferentiation. Vindoline biosynthesis in Catharanthus roseus also appears to be under this type of developmental control (Noble, 1990). Vindoline as well as the dimeric alkaloids are restricted to leaves and stems, whereas catharanthine is distributed equally throughout the above- ground and underground tissues. The developmental regulation of vindoline biosynthesis has been well documented in C. roseus seedlings, in which it is light inducible (Kutney et al., 1988). This is in contrast to catharanthine, which also accumulates in etiolated seedlings. Furthermore, cell cultures that accumulate catharanthine but not vindoline recover this ability upon redifferentiation of shoots. These observations suggest that the biosynthesis of catharanthine and vindoline is differentially regu- lated and that vindoline biosynthesis is under more rigid tissue–development and environment-specific control than is that of catharanthine. The early stages of alkaloid biosynthesis in C. roseus involve the formation of tryptamine from tryptophan and its condensation with secologanin to produce the central intermediate strictosidine, the common precursor for the monoterpenoid indole alkaloids. The enzymes catalyz- ing these two reactions are tryptophan decarboxylase (TDC) and strictosidine synthase (STR1), respectively. Strictosidine is the precursor for both the Iboga (catharanthine) and Aspidosperma (tabersonine and vindoline) types of alkaloids. The condensation of vindoline and catharanthine leads to the biosynthesis of the bisindole alkaloid vinblastine (St-Pierre et al., 1999). ● A successful attempt of production of Indole alkaloids by selected hairy root lines of C. roseus has been done. Approximately 150 hairy root clones from four varieties References Bhadra, R., Vani, S., Jacqueline, V. and Shanks (1993) Production of indole alkaloids by selected hairy root lines of Catharanthus roseus. Biotech. Bioeng. 41, 581–92. Canellos, George P. (1992) Chemotherapy of Advanced Hodgkin’s Disease with MOPP, BVD, or MOPP alternating with ABVD. N Eng J. Med. 327, 1478–84. Chu, I., Bodnar, J.A., White, E.L. and Bowman, R.N. (1996) Quantification of vincristine and vinblastine in Catharanthus roseus plants by capillary zone electrophoresis. J. Chromat. A. 755, 281–8. Danieli, B. (1998) Vinblastine-type antitumor alkaloids: a method for creating new C17 modified ana- logues. J. Org. Chem., 63, 8586–8. Garnier, F., Label, Ph., Hallard, D., Chenieux, J.C., Rideau, M. and Hamdi, S. (1996) Transgenic periwinkle tissues overproducing cytokinins do not accumulate enhanced levels of indole alkaloids. Plant Cell, Tissue Organ Culture 45, 223–30. Gurr, Sarah J. (1996) The Hidden Power of Plants. The Garden 121, 262–4. Jageti, G.C., Krishnamurthy, H. and Jyothi, P. (1996) Evaluation of cytotoxic effects of different doses of vinblastine on mouse spermatogenesis by flow cytometry. Toxicology 112, 227–36. Jordan, M.A., Thrower, D. and Wilson, L. (1991) Mechanism of Inhibition of cell proliferation by Vinca alkaloids. Cancer Res. 51, 2212–22. Jordan, M.A., Thrower, D. and Wilson, L. (1992) Effects of vinblastine, podophyllotoxin and nocodzole on mitotic spindles. J. Cell Sci. 102, 401–16. Joyce, C. (1992) What past plants hunts produced. BioScience, 42, 402. Kallio, M., Sjoblom, T. and Lahdetie, J. (1995) Effects of vinblastine and colchicine on male rat meiosis in vivo: disturbances in spindle dynamics causing micronuclei and metaphase arrest. Environ Mol Mutagen. 25, 106–17. Kutney, J.P., Choi, L.S.L., Nakano, J., Tsukamoto, H., McHugh, M. and Boulet, A. (1988) A highly effi- cient and commercially important synthesis of the antitumor catharanthus alkaloids vinblastine and leurosidine from catharanthine and vindoline. Heterocycles, 27(8), 1845–53. Madoc-Jones, H. and Mauro, F. (1968) Interphase action of vinblastine and vincristine: differences in their lethal actions through the mitotic cycle of cultured mammalian cells. J. Cell Physiol 72, 185–96. Noble, R.L. (1990) The discovery of the vinca alkaloids – chemotherapeutic agents. Biochem Cell Biol., 68, 1344–51. Pollner, F. (1990) Chemo edging up on four so-far intractable tumors: U.S. and European teams report the first clinical successes – some dramatic – from novel attacks. Medical World News 31, 13–16. Powell, J. (1991) Senior Seminar Presentation: Fall, BIOL 4900. Rowinsky, E.K. and Donehower, R.C. (1991) The clinical pharmacology and use of antimicrotuble agents in cancer therapeutics. Pharmacol. Therapeutics 52, 35–84. Terrestrial plant species with anticancer activity 53 were screened for their biosynthetic potential. Two key factors affecting productivity, growth rate and specific alkaloid yield. The detection of vindoline in these clones may potentially present a new source for the in vitro production of VBL. Production of vindoline and catharanthine by plant tissue culture and subsequent catalytic cou- pling in vitro is a possible alternative to using tissue culture alone to produce VBL and VCR. Recently, enzyme catalyzed techniques have been developed for the conversion of vindoline and catharanthine to bisindole alkaloids. Catharanthine is readily produced in cell suspension and hairy root cultures in amounts equal to or above that found in intact plant (Rajiv et al., 1993). Samuelsson, G. (1992) Drugs of Natural Origin – A textbook of Pharmacognosy. Third revised, enlarged and translated edition. Swedish Pharmaceutical Press. St-Pierre, B., Vazquez-Flota, F.A. and De Luca, V. (1999) Multicellular compartmentation of Catharanthus roseus alkaloid biosynthesis predicts intercellular translocation of a pathway intermediate. Plant Cell 11, 887–900. Viscum album (Mistletoe) Immunomodulator (Loranthaceae) Cytotoxic Location: Throughout Europe, Asia, N. Africa. It can be easily found, though not in abundant numbers. Appearance Stem: yellowish-green, branched, forming bushes 0.6–2 m in diameter. Root: Nonexistent. The plant is a semiparasitic evergreen shrub growing on branches of various tree hosts, mostly apple, poplar, ash, hawthorn and lime, more rarely on oak and pear. Leaves: opposite, tongue-shaped, yellowish-green. Flowers: small, inconspicuous, clustered in groups of three. Fruit: globular, pea-sized white berry, ripening in December. In bloom: March–May. Biology: Mistletoe is propagated exclusively by seed, which is carried distantly with the aid of birds (mostly the thrush). According to host specifity three different races can be distinguished. The plant is dioecious with very reduced male and female flowers. The life cycle of V. album is described starting from seed germination to the development of the leaves. The parasitism affords special adaptation to mineral nutrition. Tradition: Following their visions, the Druids used to cut mistletoe from trees with a golden knife at the beginning of the year. They held that the plant protected its possessor from all evil. According to a Scandinavian legend, Balder, the god of Peace, was slain with an arrow made of mistletoe. Later, however, mistletoe was rendered an emblem of love rather than hate. Its poisonous nature has been further exploited for the construction of knifes as a defensive weapon. Parts used: Leaves and young twigs. Active ingredients: viscotoxin, mistletoe alkaloids and three lectins (lactose-specific lectin, galactose-specific lectin, N-acetylgalactosamine-specific lectin). Particular value: Mistletoe preparations are well-tolerated with no significant toxicities observed so far. The status of mistletoe application in cancer therapy: Mistletoe was introduced in the treatment of cancer in 1917. Rudolf Steiner (1861–1925), founder of the Society for Cancer Research, in Arlesheim (Switzerland) was the first to mention the immunoenhancing properties of mistletoe, suggesting its use as an adjutant therapy in cancer treatment. Therapy of cancer with a Viscum extract has been carried out in Europe for over six decades in thousands of patients. Extracts from the plant are used mainly as injections. Currently, there is a number of mistletoe preparations used in many countries against different kinds of cancer: ● Iscador and Helixor are licensed medications made from plants growing on different host trees, like oak, apple, pine and fir, and administered in different kinds of cancer therapy. Some 54 Spiridon E. Kintzios et al. Iscador preparations also include metal, for example silver, mercury and copper. Iscador is usually given by injection. However, it can also be taken orally. The injection treatment typically lasts 14 days with one injection each day. It has been approved for use in Austria, Switzerland and West Germany; it apparently is also being used in France, Holland, Eastern Europe, Britain and Scandinavia. Proponents of the treatment claim that in 1978 almost 2,000,000 ampules were sold in countries where Iscador is prescribed and that about 30,000 patients are treated with it each year. Iscador is manufactured by the Verein fuer Krebsforschung (Cancer Research Association), a nonprofit organization in Arlesheim, Switzerland. ● Iscusin-Viscum preparations contain mistletoe from eight different host-trees and are produced according to a particular “rhythmic” procedure and additionally “potentialized.” Sterilization is achieved by the addition of oligodynamic silver. The indications given are: precancerous conditions, postoperative tumor prevention, operable tumors, and inoperable tumors. Each of the eight preparations (according to host-tree) has its own list of indications. Iscucin is supposed to be injected close to the tumor between 5 and 7 p.m.; the dosage and the frequency depend on body temperature. However, no preclinical studies have been published on iscucin. In the clinical field, only individual case histories are avail- able, four of which have minimal documentation, and results that can be explained without iscucin. Iscucin is produced and distributed by Wala-Heilmittel GmbH, Eckwalden. ● Isorel is an aqueous extract from whole shoots of mistletoe, the subspecies fir (Isorel A), apple (Isorel M) and pine (Isorel P) in each case. The preparation is injected hypodermically. It is usually applied for the medicative treatment of malignant tumors, postoperative and recidivation and prophylaxis of metastases, malignant illness of the hemopoietic system and defined precancerous stages. Isorel A is used principally for the treatment of male patients, while Isorel M is the respective preparation for female patients. Isorel is produced and distributed by Novipharm, Austria. However, mistletoe preparations are not approved by the US Food and Drug Administration. Precautions: It is generally recommended that treatment be stopped during menstrual period and pregnancy. According to a report of the Swiss Cancer League, fermented Iscador products contain large numbers of both dead and live bacteria and some yeast. Home-made mistletoe preparations can be very poisonous. Reported minor side-effects (for Isorel) include a small increase in temperature of 1–1.5ЊC which disappear after 1–2 days. For Helixor, if the dosage is increased too rapidly, temperature rises of 1–1.5 ЊC and headache may occur. Several clinical studies of the fermented form of Iscador have noted that patients experi- ence moderate fever (a rise of 2.3–2.4ЊC) on the day of the injections. Local reactions around the injection site, temporary headaches and chills are also associated with the fever. It is recommended to wait for the normalization of the temperature before a new injection is administered. In the case of hyperthyroidism, it is recommended to start with low doses and increase gradually. Indicative dosage and application: ● In all 11 melanoma cell lines tested: lectins isolated from V. album showed an antiproliferative effect at concentrations of 1–10 ng ml Ϫ1 , viscotoxin’s antiproliferative effect rises at concentrations of 0.5–1 ␮gml Ϫ1 and alkaloids’ antiproliferative effect begin at 10 ␮gml Ϫ1 (Yoon et al., 1998). ● Lectins ML I, ML II and ML III, at concentrations from 0.02 to 20 pg ml Ϫ1 , were able to enhance the secretion of the cytokines tumor necrosis factor (TNF) ␣, interleukin (IL)-1 ␣, IL-1 ␤ and IL-6 by human monocytes (Ziska, 1978). Terrestrial plant species with anticancer activity 55 Documented target cancers: ● Viscumin, a galactoside-binding lectin, is a powerful inflammatory mediator able to stimulate the immune system (Heiny and Benth, 1994). ● A purified lectin (MLI) from V. album has immunomodulating effects in activating monocytes/macrophages for inflammatory responses (Metzner et al., 1987). ● Viscum album L. extracts have been shown to provide a DNA stabilizing effect (Woynarowski et al., 1980). ● Since Iscador stimulates the production of the natural killer cells, it can be applied in order to stabilize the number of T4 cells and thus the clinical condition of HIV positive persons. Laboratory tests suggested that the progress of the HIV infection was inhibited (Rentea et al., 1981; Schink et al., 1992). ● Iscador has an increased action against breast cancer cells and colon cancer cells (Heiny et al., 1994). ● In most patients (but healthy individuals, as well) the quality of life increased remarkably. ● Water-soluble polysaccharides of V. album exert a radioprotective effect, which could be a valuable complement to radiotherapy of cancer. ● Iscador therapy proved to be clinically and immunologically effective and well tolerated in immuno-compromised children with recurrent upper respiratory infections, due to the Chernobyl accident (Lukyanova et al., 1992). ● When whole mistletoe preparations are employed, the effect is host tree-specific. 56 Spiridon E. Kintzios et al. Further details Related species ● The Chinese herb V. alniformosanae is the source of a conditioned medium (CM), designated as 572-CMF-, which is capable of stimulating mononuclear cells. This CM has the capacity to induce the promyelocytic cell line HL-60 to differentiate into morphologically and functionally mature monocytoid cells. Investigations have shown that 572-CM did not contain IFN-r, TNF, IL-1 and IL-2 (Chen et al., 1992). ● Hexanoic acid extracts of Viscum cruciatum Sieber parasitic on Crataegus monogyna Jacq. (I), C. monogyna Jacq. parasitized with V. cruciatum Sieber (II), and C. monogyna Jacq. Non-parasitized (III), and of a triterpenes enriched fractions isolated from I, II and III (CFI, CFII, CFIII, respectively) demonstrated significant cytotoxic activity against cultured larynx cancer cells (HEp-2 cells) (Gomez et al., 1997). Related compounds ● A galactose-specific lectin from Viscum album (VAA) was found to induce the aggregation of human platelets in a dose- and sugar-dependent manner. Small Terrestrial plant species with anticancer activity 57 non-aggregating concentrations of VAA primed the response of platelets to known aggregants (ADP, arachidonic acid, thrombin, ristocetin and A23187). VAA-induced platelet aggregation was completely reversible by the addition of the sugar inhibitor lactose and the platelets from disrupted aggregates maintained the response to other aggregants. The lectin-induced aggregation of washed platelets was more resistant to metabolic inhibitors than thrombin- or arachidonic acid-dependent cell interaction (Büssing and Schietzel, 1999). ● Partially and highly purified lectins from V. album cause a dose-dependent decrease of viability of human leukemia cell cultures, MOLT-4, after 72 h treatment. The LC50 of the partially purified lectin was 27.8 ngml Ϫ1 , of the highly purified lectin 1.3 ngml Ϫ1 . Compared to the highly purified lectin a 140-fold higher protein concentration of an aqueous mistletoe drug was required to obtain similar cytotoxic effects on MOLT-4 cells. The cytotoxicity of the highly purified lectin was preferentially inhibited by D-galactose and lactose, cytotoxicity of the mistletoe drug and the partially purified lectin were preferentially inhibited by lactose and N-acetyl-D -galactosamine (GalNAc) (Olsnes et al., 1982). ● Two lectin fractions with almost the same cytotoxic activity on MOLT-4 cells but with different carbohydrate affinities were isolated by affinity chromatography from the mistletoe drug: mistletoe lectin I with an affinity to D-galactose and GalNAc and mistletoe lectin II with an affinity to GalNAc. The lectin fractions and the mistletoe drug inhibited protein synthesis of MOLT-4 cells stronger than DNA synthesis (Olsnes et al., 1982). ● Application of an aqueous extract from Viscum album coloratum, a Korean mistletoe significantly inhibited lung metastasis of tumor metastasis produced by highly metastatic murine tumor cells, B16-BL6 melanoma, colon 26-M3.1 carcinoma and L5178Y-ML25 lymphoma cells in mice. The antimetastatic effect resulted from the suppression of tumor growth and the inhibition of tumor-induced angiogenesis by inducing TNF-alpha (Yoon et al., 1998). ● A peptide isolated from the V. album extract (Iscador) stimulated macrophages in vitro and in vivo and activated macrophages were found to have cytotoxic activity towards L-929 fibroblasts (Swiss Society for Oncology, 2001). ● Iscador Pini, an extract derived from V. album L. grown on pines and containing a non-lectin associated antigen, strongly induced proliferation of peripheral blood mononuclear cells (Cammarata and Cajelli, 1967). ● Polysaccharides are possibly involved in the pharmacological effects of V. album extracts, which are used in cancer therapy. The main polysaccharide of the green parts of Viscum is a highly esterified galacturonan whereas in Viscum ‘berries’ a complex arabinogalactan is predominant and interacting with the galactose-specific lectin (ML I) (Stein, 1999). ● Water-soluble polysaccharides of V. album were shown to exert a radioprotective effect which was a function of both the radiation dose and the drug dose and time of its injection. The maximum radioprotective efficacy of polysaccharides was observed after their injection 15 min before irradiation (Stein, 1999). 58 Spiridon E. Kintzios et al. Antitumor activity ● The Korean mistletoe extract possesses antitumor activity in vivo and in vitro. Antiproliferative activities have been attributed to Viscum album C, Viscum album Qu and Viscum album M (trade name Iscador) on melanoma cell lines. Viscum album C contains viscotoxin, alkaloids and lectins. Viscum album Qu was extracted by Medac (Germany). Viscum album M is a preparation by the Institute Hiscia (Switzerland). The antiproliferative effect of the extracts on 11 melanoma cell lines obtained through the EORTC-MCG were tested in monolayer proliferation tests. In most of the melanoma cell lines tested, there was a significant antiproliferative effect of V. album C at a concentration of 100␮gml Ϫ1 , whereas V. album M showed an antiproliferative effect at 1,000 ␮gml Ϫ1 . The lectins isolated from V. album C, when compared with each other showed almost in all 11 melanoma cell lines tested a similar antiproliferative effect. It was seen at concentrations of 1–10 ng ml Ϫ1 . The antiproliferative effect of viscotoxin rises at concentrations of 0.5–1 ␮gml Ϫ1 , whereas the antiproliferative effect of alkaloids begins at 10 ␮gml Ϫ1 (Yoon et al., 1998). ● Iscador inhibited 20-methylcholanthrene-induced carcinogenesis in mice. Intraperitoneal administration of Iscador (1 mgdose Ϫ1 ) twice weekly for 15 weeks could completely inhibit 20-methylcholanthrene-induced sarcoma in mice and protect these animals from tumour-induced death. Iscador was found to be effective even at lowered doses. After administration of 0.166, 0.0166 and 0.00166 mgdose Ϫ1 , 67, 50 and 17% of animals, respectively, did not develop sarcoma (Kuttan et al., 1997). ● Patients with advanced breast cancer who were treated parenterally with Iscador showed an improvement in repair, possibly due to a stimulation of repair enzymes by lymphokines or cytokines secreted by activated leukocytes or an alteration in the susceptibility to exogenic agents resulting in less damage (Kovacs et al., 1991). ● Macrophages from mice treated with V. album extract were shown to be active in inhibiting the proliferation of tumor cells in culture. These activated macrophages have now been shown to protect mice from dying of progressive tumors when injected intraperitoneally into the animals. Prophylactic as well as multiple treatments with macrophages activated with V. album extract seemed more effective than a single treatment. Thus, in addition to a direct cytotoxic effect of V. album extract, the activation of macrophages may contribute to the overall antitumor activity of the drug (Kuttan, 1993). ● Iscador was found to be cytotoxic to animal tumor cells such as Dalton’s lymphoma ascites cells (DLA cells) and Ehrlich ascites cells in vitro and inhibited the growth of lung fibroblasts (LB cells), Chinese hamster ovary cells (CHO cells) and human nasopharyngeal carcinoma cells (KB cells) at very low concentrations. Moreover, administration of Iscador was found to reduce ascites tumors and solid tumors produced by DLA cells and Ehrlich ascites cells. The effect of the drug could be seen when the drug was given either simultaneously, after tumor development or when given prophylactically, indicating a mechanism of action very different from other chemotherapeutic drugs. Iscador was not found to be cytotoxic to lymphocytes (Luther et al., 1977). ● The ML-I lectin from V. album has been shown to increase the number and cytotoxic activity of natural killer cells and to induce antitumor activity in animal models. The Terrestrial plant species with anticancer activity 59 same lectin inhibits cell growth and induces apoptosis (programmed cell death) in several cell types (Janssen et al., 1993). ● In mice, an increased number of plaque-forming cells to sheep red blood cells (SRBC) followed the injection of Isorel (Novipharm, Austria) together with SRBC. Further, survival time of a foreign skin graft was shortened if Isorel was applied at the correct time. Finally, suppressed immune reactivity in tumorous mice recovered following Isorel injection. Isorel was further shown to be cytotoxic to tumor cells in vitro. Its application to tumor-bearing mice could prolong their life but without any therapeu- tic effect. However, a combination of local irradiation and Isorel was very effective: following 43Gy of local irradiation to a transplanted methylcholanthrene-induced fibrosarcoma (volume about 240mm 3 ) growing in syngeneic CBA/HZgr mice, the tumor disappeared in about 25% of the animals; the addition of Isorel increased the incidence of cured animals to over 65%. The combined action of Isorel, influencing tumor viability on the one hand and the host’s immune reactivity on the other, seems to be favorable for its antitumor action in vivo (Pouckova et al., 1986). Anti-leukemic activity ● Mistletoe lectin I from V. album applied in vitro for 1h in appropriate doses, caused irreversible inhibition of leukemic L1210 cell proliferation. The toxin appeared to be cytotoxic to normal bone marrow progenitor cells, as well as observed to the P-388 and L1210 leukemia cells. ● Iscador was found to reduce the leukocytopenia produced by radiation and cyclophosphamide treatment in animals. Weight loss due to radiation was considerable whereas weight loss due to cyclophosphamide was not altered. Hemoglobin levels also were not affected, indicating that treatment with the extract reduces lymphocy- topenia and hence could be used along with chemotherapy and radiation therapy (Kutten et al., 1993). Other medical effects ● The 5-bromo-2Ј-deoxyuridine-induced sister chromatid exchange (SCE) frequency of amniotic fluid cells (AFC) remained stable after the addition of a therapeutical concentration of V. album (Iscador P) but decreased significantly after administration of high drug doses. As the proliferation index remained stable, even at extremely high drug concentrations, this effect could not be ascribed to a reduction of proliferation. No indications of cytogenetic damage or effects of mutagenicity were seen after the addition of the preparation. In addition, increasing concentrations of V. album L. extracts were shown to significantly reduce SCE frequency of phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC) of healthy individuals (Bussing et al., 1995). ● The three mistletoe lectins. ML I, ML II and ML III, at concentrations from 0.02 to 20pgml Ϫ1 (100–10,000-fold lower than those showing toxic effects) were able to enhance the secretion of the cytokines tumor necrosis factor (TNF) alpha, interleukin (IL)-1 alpha, IL-1 beta and IL-6 by human monocytes several-fold over References Barney, C.W., Hawksworth, F.G. and Geils, B.W. (1998) Hosts of Viscum album. Eur. J. For. Path. 28, 187–208. Büssing, A. (2000) Mistletoe: The genus Viscum. Harwood Academic Publishers. Büssing, A., Schaller, G. and Pfuller, U. (1998) Generation of reactive oxygen intermediates (ROI) by the thionins from Viscum album L. Anticancer Res. 18, 4291–6. Büssing, A. and Schietzel, M. (1999) Apoptosis-inducing properties of Viscum album L. Extracts from different host trees, correlate with their content of toxic Mistletoe lectins. Anticancer Res. 19, 23–8. CA (Anonymous) (1983) Unproven methods of cancer management: Iscador. CA: a Cancer J. Clinicians, 33, 186–8. Cammarata, P.L. and Cajelli, E. (1967) Free amino acid content of Viscum album L. berries parasitizing the Pinus silvestris L. and Pinus nigra Arnold var. austriaca. Boll. Chim. Farm. Aug. 106(8), 521–6. Chen, P.M., Hsiao, K.I., Su, J.L., Liu, J. and Yang, L.L. (1992) Study of the activities of Chinese herb Viscum alniformosanae Part II: The components of conditioned medium produced by Viscum alniformosanae-stimulated mononuclear cells. Am. J. Chin. Med. 20(3–4), 307–12. Fink, J.M. (1988) Third Opinion: An International Directory to Alternative Therapy Centers for the Treatment and Prevention of Cancer and Other Degenerative Diseases. Second edn. Garden City Park, New York: Avery Publishing Group Inc., p.137. Franz, H. (1986) Mistletoe lectins and their A and B chains. Oncology 43(1), 23–34. Grieve, M. (1994) A Modern herbal. Edited and introduced by Mrs. C.F. Leyel, Tiger books international, London. Gomez, M.A, Saenz, M.T., Garcia, M.D., Ahumada, M.C. and De La Puerta, R. (1997) Cytostatic activity against Hep-2 cells of methanol extracts from Viscum cruciatum Sieber parasitic on Crataegus monogyna Jacq. and two isolated principles. Phytother. Res. 11, 240–2. Gorter, R. (1994) The European Mistletoe (Viscum album): new studies show significant results for AIDS and immune system problems. Institute for Oncological and Immunological Research. Hauser, S. and Kast, A. (2001) Iscusin – preparations for pre- and postoperative treatment of malignant tumours. (BCCA Cancer Information Centre search file 701). Hauser, S.P. (1993) Unproven methods in cancer treatment. Curr. Opinion Oncol. 5, 646–54. Heiny, B.M. and Benth, J. (1994) Mistletoe extract standardized for the galactoside-specific lectin (ML-1) induces B-endorphin release and immunopotentiation in breast cancer patients. Anticancer Res. 14, 1339–42. Janssen, O., Scheffler, A., Kabelitz, D. (1993) In vitro effects of mistletoe extracts and mistletoe lectins. Cytotoxicity towards tumor cells due to the induction of programmed cell death (apoptosis). Arzneimittelforschung 43(11), 1221–7. Kovacs, E., Hajto, T. and Hostanska, K. (1991) Improvement of DNA repair in lymphocytes of breast cancer patients treated with Viscum album extract (Iscador). Eur. J. Cancer 27(12), 1672–6. Kuttan, G., Menon, L.G., Antony, S. and Kuttan, R. (1997) Anticarcinogenic and antimetastatic activity of Iscador. Anticancer Drugs Apr. 8(Suppl 1), S15–16. 60 Spiridon E. Kintzios et al. control values were observed. The immunoactivating concentrations by the three lectins were found different for each donor. At toxic concentrations, the amounts of IL-1 alpha, IL-1 beta and to a less extent of TNF alpha in monocytes supernatants were particularly high (Ziska, 1998). ● The mistletoe lectin ML-A inactivates rat liver ribosomes by cleaving a N-glycosidic bond at A-4324 of 28S rRNA in the ribosomes, as it is characteristic of the common ribosome-inactivating proteins (RIPs) (Citores et al., 1993). ● During a phase I/II study to determine the effect of V. album (Iscador) in HIV infection, 40 HIV-positive patients (with CD4-lymphocyte count Ͼ200) were injected with 0.01 mg up to 10mg subcutaneously twice a week over a period of 18 weeks. The extract was well tolerated and suggested to have anti-HIV activities (Gorter, 1994). Lukyanova, M., Chernyshov, P., Omelchenko, I., Slukvin, I., Pochinok, V., Antipkin, G., Voichenko, V., Heusser, P. and Schneiderman, G. (1992) Research on immune-suppressed children following the Chernobyl accident. Mistletoe effective for Chernobyl children. Ukrainian Institute for Pediatrics, Lukas Klinik, Switzerland. Luther, P., Franz, H., Haustein, B. and Bergmann, K.C. (1977) Isolation and characterization of mistletoe extracts (Viscum album L.). II. Effect of agglutinating and cytotoxic fractions on mouse ascites tumor cells. Acta Biol Med Ger 36(1), 119–25. Metzner, G., Franz, H., Kindt, A., Schumann, I. and Fahlbusch, B. (1987) Effects of lectin I from mistletoe (ML I) and its isolated A and B chains on human mononuclear cells: mitogenic activity and lymphokine release. Pharmazie May 42(5), 337–40. Mueller, A.E. and Anderer, A.F. (1990) A Viscum album oligosaccharide activating human natural cytotoxicity is an interferon ␥ inducer. Cancer Immunol Immunother. 32, 221–7. Olsnes, S., Stirpe, F., Sandvig, K. and Pihl, A. (1982) Isolation and characterization of viscumin, a toxic lectin from Viscum album L. (Mistletoe). J. Biol. Chem. 257(22), 13263–70. Ontario Breast Cancer Information Exchange Project (1994) Guide to unconventional cancer therapies. First edn. Ontario Breast Cancer Information Exchange Project, Toronto. 76–79. Rentea, R., Lyon, E. and Hunter, R. (1981) Biologic properties of iscador: a Viscum album preparation I. Hyperplasia of the thymic cortex and accelerated regeneration of hematopoietic cells following X-irradiation. Lab. Invest. Jan. 44(1), 43–8. Samuelsson, G. (1992) Drugs of Natural Origin – A Textbook of Pharmacognosy. Third revised, enlarged and translated edition. Swedish Pharmaceutical Press. Schink, M., Moser, D. and Mechelke, F. (1992) Two-dimensional isolectin patterns of the lectins from Viscum album L. (mistletoe). Naturwissenschaften Feb. 79(2), 80–1. Stein, M.G., Edlund, U., Pfuller, U., Bussing, A. and Schietzel, M. (1999) Influence of polysaccharides from Viscum album L. on human lymphocytes, monocytes and granulocytes in vitro. 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Terrestrial plant species with anticancer activity 61 [...]... behind the foliage Parts used: bark, stem Active ingredients G G Flavonols: 5 ,3 -dihydroxy -3 , 6,7,8,4Ј-pentamethoxyflavone, 5-hydroxy -3 , 6,7,8 ,3 ,4Ј-hexamethoxyflavone, digicitrin, 3- O-demethyldigicitrin, 3, 5 ,3 -trihydroxy-6,7,8,4Ј-tetramethoxyflavone and 3, 5-dihydroxy-6,7,8 ,3 ,4Ј-pentamethoxyflavone Alkaloids: 1,2 , 3- trimethoxy-10-methyl-acridone, 1 ,3, 4-trimethoxy-10-methyl-acridone, des-Nmethyl acronycine,... cancer cell line (MCF-7) (Gu et al., 19 93) From A bullata, three more pairs of new ketolactone Annonaceous acetogenins were isolated by bioactivity-directed isolation They are hydroxylated adjacent bis-THF acetogenins and are named (2,4-cis and trans ) -3 2-hydroxybullatacinone (1 and 2), (2,4cis and trans ) -3 1-hydroxybullatacinone (3 and 4), and (2,4-cis and trans ) -3 0-hydroxybullatacinone The structures... (1996) Taxol from Pestalotiopsis microspora, an endophytic fungus of Taxus wallachiana Microbiology 142, 435 –440 Sho-saiko-to, Juzen-taiho-to Sho-saiko-to (SST) and Juzen-taiho-to ( JTT) are not plants but Japanese modified Chinese herbal medicines, or Kampo Juzen-taiho-to was formulated by Taiping Hui-Min Ju (Public Welfare Pharmacy Bureau) in Chinese Song Dynasty in AD 1200 It is prepared by extracting... effect of sodium L-malate, an active constituent isolated from Angelicae radix, on cis-diamminedichloroplatinum(II)-induced toxic side effect Chem Pharm Bull (Tokyo) 42(12), 2565–8 Tatsuta, M., Iishi, H., Baba, M., Nakaizumi, A and Uehara, H (1994) Inhibition by shi-quan-da-bu-tang (TJ-48) of experimental hepatocarcinogenesis induced by N-nitrosomorpholine in Sprague-Dawley rats Eur J Cancer 30 (1), 74–8... immunologically active substances in Juzen-taiho-to Gan To Kagaku Ryoho 16(4 Pt 2-2 ), 1500–5 Yano, H., Mizoguchi, A., Fukuda, K., Haramaki, M., Ogasawara, S., Momosaki, S and Kojiro, M (1994) The herbal medicine sho-saiko-to inhibits proliferation of cancer cell lines by inducing apoptosis and arrest at the G0/G1 phase Cancer Res 54(2), 448–54 Zee-Cheng, R.K (1992) Shi-quan-da-bu-tang (ten significant tonic decoction),... hard Part used: stem segments, needles 1–2 cm long, and roots Active ingredients: G G G Taxane diterpenes, among them paclitaxel (earlier known as taxol), cephalomannine Key precursors: baccatin III, 10-desacetylbaccatin III, 9-dihydrobaccatin 1 3- Acetyl-9-dihydrobaccatin III, baccatin VI Related compounds, such as taxotere Figure 3. 3 Taxus III, Terrestrial plant species with anticancer activity 63 Particular... (2,4-cis and trans )-1 0-hydroxybullatacinone (1 and 2), (2,4-cis and trans )-1 2-hydroxybullatacinone (3 and 4), and (2,4-cis and trans )-2 9-hydroxybullatacinone These mixtures all showed potent activities in the BST and exhibited cytotoxicities comparable to those of adriamycin against human solid tumor cells in culture with selectivities exhibited especially toward the breast cancer cell line (MCF-7)... CDDP-induced nephrotoxicity and bone marrow toxicity without reducing the antitumor activity Water-soluble related compounds of the herbal medicine SST dose-dependently inhibited the proliferation of a human hepatocellular carcinoma cell line (KIM-1) and a cholangiocarcinoma cell line (KMC-1) Fifty percent effective doses on day 3 of exposure to SST were 35 3.5 ϩ/Ϫ 32 .4 ␮g mlϪ1 for KIM-1 and 236 .3 ϩ/Ϫ... contains acrovestone and bauerenol, two crystalline substances (Wu et al., 1989; Zhu et al., 1989) Acronychia baueri (Rutaceae): the bark contains the alkaloids, 1,2 , 3- trimethoxy-10methyl-acridone, 1 ,3, 4-trimethoxy-10-methyl-acridone, des-N-methyl acronycine, normelicopine and noracronycine (Svoboda et al., 1966) Acronychia laurifolia BL: contains acronylin, a phenolic compound (Biswas et al., 1970) Acronychia... (PC -3 ) and pancreatic carcinoma (PACA-2) cell lines (Kim et al., 1998) Annona senegalensis is used against sarcomas (Durodola et al., 1975a,b) Annona purpurea contains alkaloids (Sonnet et al., 1971) Annona reticulata: seeds contain the cytotoxic gamma-lactone acetogenin, cis-/trans-isomurisolenin, along with annoreticuin, annoreticuin-9-one, bullatacin, squamocin, cis-/trans-bullatacinone and cis-/trans-murisolinone . Microbiology 142, 435 –440. Sho-saiko-to, Juzen-taiho-to Sho-saiko-to (SST) and Juzen-taiho-to ( JTT) are not plants but Japanese modified Chinese herbal medicines, or Kampo. Juzen-taiho-to was formulated. line (KIM-1) and a cholangiocarcinoma cell line (KMC-1). Fifty percent effective doses on day 3 of exposure to SST were 35 3.5 ϩ/Ϫ 32 .4 ␮gml Ϫ1 for KIM-1 and 236 .3 ϩ/Ϫ26.5␮gml Ϫ1 for KMC-1. However, almost. III, 10-desacetylbaccatin III, 9-dihydrobaccatin III, 1 3- Acetyl-9-dihydrobaccatin III, baccatin VI. ● Related compounds, such as taxotere. 62 Spiridon E. Kintzios et al. Figure 3. 3 Taxus. Particular